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Aug 19, 2010

Viral Link to Cancer May Be Hidden as Host Oncogenes Kick Out Pathogen’s Genome

  • Researchers have published new evidence supporting the hypothesis that some viruses might act to trigger the initiation of cancer formation but then disappear without trace by the time the cancer has been diagnosed. Their research in mice has also confirmed that vaccinating animals against one cancer-causing virus protects against subsequent cancer development.

    The University of Cambridge team concludes that this ‘hit and run’ hypothesis of virus-mediated cancer activation could also mean that a number of different malignancies have so far unidentified viral infections as either their triggers or accessory factors. If this is the case, then antiviral vaccination might provide a relatively simple approach to preventing the formation of potentially diverse cancers. The research is published in the Journal of General Virology in a paper titled "Vaccination Against a Hit-and-Run Viral Cancer."

    Some cancers have well-established connections with viral infection, but although gammaherpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are known to be oncogenic, the lack of unifying features of the associated cancers hasn’t helped clarify how the infection and resulting disease are linked or what vaccination might achieve, explain Philip Stevenson, Ph.D,. and Stacey Efstathiou, Ph.D., at the university’s division of virology and department of pathology. Moreover, Burkitt's lymphoma has been shown to be more strongly associated with c-myc translocation than with EBV infection, suggesting that while the viral genes play a triggering or accessory role in the disease, it is the host’s oncogenes that represent the main drivers of cancer proliferation.

    The hit and run hypothesis proposes that cumulative host mutations in cancer cells eventually overwhelm the original viral genes, causing these genomes to be lost entirely. If verified, this hit and run effect could also mean that the known virus-associated cancers potentially represent only a fraction of those to which a viral infection played an initial contributing role.

    The problem, the authors point out, is that to date there has been a lack of experimental evidence supporting this hypothesis. To investigate the validity of the hit and run hypothesis further, the Cambridge team used Cre–lox recombination in a well-established conditional mouse cancer model to transform virus-infected cells, and then analyzed the emerging cancers for viral genome retention.

    The results showed that the resulting cancers rapidly lost any sign of viral infection, but vaccinating them with a modified version of the same virus protected them against subsequent cancer development. "Our data show that cells driven to proliferate by host oncogenes readily lose gammaherpesvirus genomes in vivo," the authors state.

    "Relying on viral genome detection to establish etiology could therefore underestimate the number of cancers to which gammaherpesviruses contribute; the retention of viral genomes by some cancer types does not establish that viral genome retention is the norm." They further admit that as there is "no certain way to identify a human cancer as previously virus-positive once it becomes virus-negative, human gammaherpesvirus disease burdens may only be revealed by vaccination."

     


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